WO2009021931A1 - Vaccines - Google Patents
Vaccines Download PDFInfo
- Publication number
- WO2009021931A1 WO2009021931A1 PCT/EP2008/060505 EP2008060505W WO2009021931A1 WO 2009021931 A1 WO2009021931 A1 WO 2009021931A1 EP 2008060505 W EP2008060505 W EP 2008060505W WO 2009021931 A1 WO2009021931 A1 WO 2009021931A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- protein
- malaria
- use according
- rts
- vaccine
- Prior art date
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Definitions
- the present invention relates to a novel use of a malaria antigen to immunise against malarial disease.
- the invention relates in particular to the use of circumsporozoite (CS) protein from P. falciparum or fragments thereof, to immunise infants against malarial disease.
- CS circumsporozoite
- Malaria is one of the world's major health problems.
- economic and social development, together with anti malarial campaigns have resulted in the eradication of malaria from large areas of the world, reducing the affected area of the world surface from 50% to 27%. Nonetheless, given expected population growth it is projected that by 2010 half of the world's population, nearly 3.5 billion people, will be living in areas where malaria is transmitted .
- Current estimates suggest that there are well in excess of 1 million deaths due to malaria every year, and the economic costs for Africa alone are thought to be staggering and in the region of at least several billion US dollars annually .
- Plasmodium The life cycle of Plasmodium is complex, requiring two hosts, man and mosquito for completion.
- the infection of man is initiated by the introduction of sporozoites from the saliva of a biting and infected mosquito.
- the sporozoites migrate to the liver and there infect hepatocytes where they differentiate and multiply, via the exoerythrocytic intracellular stage, into the merozoite stage which infects red blood cells (RBC) to initiate cyclical replication in the asexual blood stage.
- RBC red blood cells
- the cycle is completed by the differentiation of a number of merozoites in the RBC into sexual stage gametocytes, which are ingested by the mosquito, where they develop through a series of stages in the midgut to produce sporozoites which migrate to the salivary gland.
- the sporozoite stage of Plasmodium has been identified as a potential target of a malaria vaccine.
- Vaccination with inactivated (irradiated) sporozoite has been shown to induced protection against experimental human malaria (Am. J, Trop. Med. Hyg 24: 297-402, 1975).
- CS protein circumsporozoite protein
- the CS protein of Plasmodia species is characterized by a central repetitive domain (repeat region) flanked by non-repetitive amino (N-terminus) and carboxy (C-terminus) fragments.
- the CS protein in P. falciparum has a central repeat region that is highly conserved.
- WO 93/10152 and WO 98/05355 describe a vaccine derived from the CS protein of P. falciparum and it clear that there has been some progress made towards the vaccination against P. falciparum using the approach described therein, see also Heppner et al. 2005, Vaccine 23, 2243-50.
- the CS protein from P. falciparum has been cloned, expressed and sequenced for a variety of strains for example the NF54 strain, clone 3D7 (Caspers et al., MoI. Biochem. Parasitol. 35, 185-190, 1989).
- the protein from strain 3D7 is characterised by having a central immunodominant repeat region comprising a tetrapeptide Asn-Ala-Asn-Pro repeated 40 times but interspersed with four minor repeats Asn- VaI- Asp-Pro. In other strains the number of major and minor repeats varies as well as their relative position. This central portion is flanked by an N and C terminal portion composed of non- repetitive amino acid sequences designated as the repeatless portion of the CS protein.
- GlaxoSmithKline Biologicals' RTS S malaria vaccine based on CS protein has been under development since 1987 and is currently the most advanced malaria vaccine candidate being studied .
- This vaccine specifically targets the pre-erythrocytic stage of P. falciparum, and confers protection against infection by P. falciparum sporozoites delivered via laboratory-reared infected mosquitoes in malaria-na ⁇ ve adult volunteers, and against natural exposure in semi-immune adults 5 ' 6 .
- RTS,S/AS02A RTS, S plus adjuvant system
- WO 2006/029887 describes use of RTS, S to treat severe malaria in children 1 to 4 years of age.
- Severe malaria disease is described in the WHO guide to clinical practice (Page: 4 World Health Organization. Management of severe malaria, a practical handbook. Second edition, 2000. http://mosquito.who.int/docs/hbsm.pdf). Classification of children according to the WHO-based definition for severe malaria identifies children who are very sick and at high risk of dying. High risk may be taken to mean about a 30% or greater risk dying.
- the present invention provides the use of an antigen derived from the CS protein of Plasmodium falciparum in combination with a pharmaceutically acceptable adjuvant, in the manufacture of a medicament for vaccinating infants against malaria.
- Figure 1 shows an outline of the study design for trial 038
- Figure Ia shows an outline of the trial design
- Figure 2a shows incidence of general reactogenicity
- Figure 2b shows incidence of local reactogenicity
- Figure 2c shows proportion of doses with solicited general symptoms reported during the 7 days post vaccination
- Figure 3 shows vaccine efficacy data.
- Figure 4 shows a Kaplan-Meier curve for 038 trial
- Figure 5a shows a Kaplan-Meier curve for 026 trial (comparison data)
- Figure 5b shows a Kaplan-Meier curve for 026 trial (comparison data)
- Figure 3 the table presents estimates of VE over a follow-up from 14 days post dose 3 of RTSS or Engerix until month 6 (cross-sectional visit) for the ATP cohort. This includes subjects that received at least 3 doses of RTS, S or Engerix-B, clearance drug and have follow-up time in ADI. Both estimates of VE against infection and disease are presented. Protocol Exploratory endpoint evaluating disease over a time-frame from month 0 (day of first vaccination) to month 6 for the ITT cohort is presented Disease 3.
- PYAR Episodes/Person Years at Risk
- falciparum asexual parasitemia > 500 per ⁇ L and the presence of fever > 37.5°C in a child who is unwell and brought for treatment (ITT 0-6) Adjusted estimates for area and distance from health center Malaria in the context of this specification is intended to refer to malaria infection (defined below) and/or clinical malaria disease (also defined below).
- the vaccination according to the invention provides a reduced risk of malaria infection.
- the calculated reduction in risk of infection after vaccination is at least about 30, 40, 50%, for example 60 such as 65%.
- the vaccination according to the invention provides a reduced risk of developing clinical symptoms of malaria.
- the risk of clinical disease after receiving, for example three doses in a 3 month study interval may be reduced by at least about 30, 40, 50%, for example 60 such as approximately 65% following the third dose.
- the malaria is non-severe malaria.
- the vaccination provides a reduced risk of developing the following clinical disease symptoms: any level of P. falciparum asexual parasitemia and the presence of fever > 37.5°C or a history of fever within 24 hours.
- the reduced risk of malaria infection and/or reduced risk of developing clinical symptoms of malaria is assessed over the 3 months after final vaccination.
- the vaccine may be administered at appropriate intervals, for example 2, 3, 4 or 5 week intervals such as 4 week intervals as one, two or three doses.
- the calculated efficacy of the malaria vaccine employed in the 038 study was about 65% (adjusted vaccine efficacy) against clinical malaria (that is general/non-severe) in comparison to the control group (data in Table 3).
- This efficacy is about 30% higher than the efficacy, observed in older children, against clinical non- severe disease results of the 026 trial, where the efficacy against non-severe malaria was between 30 and 35%.
- the latter figures reflect efficacy against non-severe clinical malaria symptoms and not efficacy against severe malaria, which was performed as a sub-analysis in the 026 trial.
- the vaccination of the present invention seems to translate into a reduction of the risk of acquiring non-severe clinical form of malaria in comparison to the control group in this study and furthermore in comparison vaccinated older children in the 026 trial.
- Clinical malaria is defined herein as fever greater than or equal to 37.5°C with an asexual parasitaemia of P '. falciparum of 500 present per ⁇ L of blood or more (for example with a sensitivity and specificity of greater than 90%).
- the efficacy data in the two trials (038, see Table 3, and 026) was derived from observations periods that differed in length. Malaria infection in this context is intended to refer to any asexual Plasmodium falciparum parasitaemia detected by active detection of infection (ADI) or passive case detection (PCD).
- ADI active detection of infection
- PCD passive case detection
- infant in the context of this specification is under 1 year such as about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50 weeks old. More specifically, about 10, about 14 and/or about 18 weeks old.
- a first vaccination is given to an infant at approximately 6 to 10 weeks after birth, such as 10 weeks.
- a second vaccination is given to an infant at approximately 10 to 14 weeks after birth, such as 14 weeks.
- a third vaccination is given to an infant at approximately 14 to 18 weeks after birth, such as 16-18 weeks.
- a boosting vaccination may be provided after the first course vaccination has been administered. This boost may be administered 6 to 24 months after completion of said primary course. Whilst not wishing to be bound by theory, the evidence available in this 038 trial does not suggest the anti CS titers were significantly different to those observed in the 026 trial, even though a trend toward higher GMT is seen in 038 for data up to 3 months post dose 3.
- Na ⁇ ve in the context of this specification is intended to mean that the infant has no or very low detectable antibodies to the CS protein, for example as determined by ELISA or that the infant is so young that it is reasonable to believe that it has not experienced infection by P. falciparum parasites post natal.
- a low level is below the cut off level defined for a relevant anti CS ELISA. See for example Gorden et al J. Infectious Disease 1995; 171 :1576-1585 or Stout el al J.
- At least 65% of the infants treated with the vaccine are na ⁇ ve, such as 75, 85, 90, 95 or 99%.
- the invention provides a use of the vaccination for generating an appropriate antibody response to a CS protein, for example wherein 80, 85, 90, 95, 96, 97 or 98% of infants vaccinated according to the invention have anti-CS antibodies above the defined cut off limit for relevant ELISA (such as that used by GSK in clinical trials), about one month to about 4 months after receiving the last vaccination, such as one month and 4 months thereafter.
- the antibody response is sufficient to provide a reduced risk of malarial infection and/or a reduced risk of clinical malaria in the vaccinated infant.
- the invention provides use of a vaccine for delaying infections of an infant with malaria parasites and/or delaying the development of clinical symptoms of malaria.
- the time to the first malaria infection episode or clinical malaria can, for example be measured using a Cox regression model.
- the invention is particularly concerned with reducing the incidence of clinical malaria from P. falciparum, such as severe and/or mild forms thereof. Nevertheless in one aspect the invention provided protection against clinical symptoms of non-severe malaria.
- Non-severe malaria is herein defined as all clinical cases of malaria that are not severe.
- the CS antigens according to the invention may be used in conjunction with another antigen selected from any antigen which is expressed on the sporozoite or the pre- erythrocytic stage of the parasite life cycle such as the liver stage, for example liver stage antigen- 1 (LSA-I), liver stage antigen-3 (LS A-3), thrombospondin related anonymous protein (TRAP), merozoite surface protein- 1 (MSPl) the major merozoite surface protein, and apical merezoite antigen- 1 (AMA-I) which has recently been show to be present at the liver stage (in addition to the erythrocytic stage). All of these antigens are well known in the field.
- the antigen may be the entire protein or an immunogenic fragment thereof. Immunogenic fragments of malaria antigens are well know, for example the ectodomain from AMA-I .
- the P. falciparum antigen is fused to the surface antigen from hepatitis B (HBsAg).
- HBsAg hepatitis B
- a circumsporozoite (CS) protein antigen suitable for use in the present invention is in the form of a fusion protein with HBsAg.
- the antigen may be the entire CS protein from P. falciparum or part thereof, including a fragment or fragments of the CS protein, which may be fused together.
- the CS protein based antigen is in the form of a hybrid protein comprising substantially all the C-terminal portion of the CS protein of P. falciparum, four or more tandem repeats of the CS protein immunodominant region, and the surface antigen from hepatitis B (HBsAg).
- the fusion protein comprises a sequence which contains at least 160 amino acids which is substantially homologous to the C- terminal portion of the CS protein.
- the C terminal portion of the CS protein includes the C terminus devoid of the hydrophobic anchor sequence.
- the CS protein may be devoid of the last 12 to 14 (such as 12) amino-acids from the C terminal.
- the fusion protein for use in the invention is a protein which comprises a portion of the CS protein of P '. falciparum substantially as corresponding to amino acids 207-395 of P. falciparum 3D7 clone, derived from the strain NF54 (Caspers et al, supra) fused in frame via a linear linker to the N-terminal of HBsAg.
- the linker may comprise part or all of the preS2 region from HBsAg.
- a suitable CS constructs for use in the present invention are as outlined in WO 93/10152.
- Particularly suitable is the hybrid protein known as RTS as described in WO 93/10152 (wherein it is denoted RTS*) and WO 98/05355, the whole contents of both of which are incorporated herein by reference.
- RTS hybrid protein known as RTS as described in WO 93/10152 (wherein it is denoted RTS*) and WO 98/05355, the whole contents of both of which are incorporated herein by reference.
- a particularly suitable fusion protein is the fusion protein known as RTS which consists of:
- Met Ala Pro Three amino acids, Met Ala Pro, derived from a nucleotide sequence (1062 to 1070) created by the cloning procedure used to construct the hybrid gene.
- the RTS is in the form of immunogenic particles of RTS, S.
- the RTS, S construct may for example comprises two polypeptides RTS and S that are synthesized simultaneously and spontaneously form composite particulate structures (RTS 5 S).
- the RTS protein is preferably expressed in genetically engineered yeast cells, most preferably S. cerevisiae or Picha pastoris . In such a host, RTS will be expressed as lipoprotein particle (also referred to herein as immunogenic particle or a virus like particle).
- the preferred recipient yeast strain preferably already carries in its genome several integrated copies of a hepatitis B S expression cassette. The resulting strain synthesizes therefore two polypeptides, S and RTS, that spontaneously co-assemble into mixed (RTS, S) lipoprotein particles. These particles, advantageously present the CSP sequences of the hybrid at their surface.
- the ratio of RTS: S in these mixed particles is, for example 1 :4.
- the hybrid protein may contain an N-terminal fragment from the CS protein of P. falciparum.
- the hybrid protein may comprise one or more repeat units from the central region of P. falciparum. For example 1, 2, 3, 4, 5, 6, 7, 8, 9 or more repeat units.
- the hybrid protein may contain a C-terminal fragment from the CS protein of P. falciparum.
- N and C terminus and the central repeat fragments may include several T and B cell epitopes.
- recombinant proteins often unnatural amino acids are introduced in the cloning process and are observed in the final expressed protein. For example several such as 1, 2, 3, 4 or 5 amino acids may be inserted at the beginning (N -terminus) of the protein. If 4 amino acids are inserted at the beginning of the protein they may for example be MMAP. In addition to or alternatively 1 , 2, or 3 such as 1 amino acids may be inserted into the body/middle of the protein, provided that the activity and properties, such as immunogenicity, of the protein are not adversely affected.
- the use of the malaria vaccine described here may also be in combination with one or more other vaccines commonly administered to infants less than 1 year of age, for example to provide protection against one or more the following: diphtheria, tetanus, pertusis, measles, oral polio and/or Hepatitis B.
- vaccines may be given at age 1, 2, 3, 4, 5, 6, 7, 8, or 9 months as appropriate such as 6, 10 and 14 weeks.
- said infant vaccine provided is DTPw-Hib optionally with an oral polo vaccine.
- the malaria vaccine according to the invention may also be used in combination with a BCG vaccine, for example given 1, 2 or more weeks before the vaccine of the invention.
- Vaccines such as oral polio, BCG and/or Hepatitis B vaccine may be given at about 1 week or less post natal.
- the vaccines may be given simultaneously or about 15, 20, 25 or more days apart. The latter may avoid any adverse interaction of the two or more vaccines.
- the invention also relates to a method of treatment comprising administering a therapeutically effective amount of a vaccine as described herein, to infants to provide protection against infection and/or developing clinical malaria.
- a suitable vaccination schedule for use in the invention includes the administration of 3 doses of vaccine, at one month intervals.
- one, two, three or more doses are employed, given 1, 2, 3, 4, 5, 6, 7, 8 or more weeks apart.
- Boosting of the same may be employed to complement the above primary course of vaccination. It may also be appropriate to use general good practice for the prevention of malaria in conjunction with the malaria vaccine described herein. Best practice would include practices such spraying bedrooms etc with insecticides and/or employing a bed net to reduce the exposure of the individual to the mosquitoes. In the 038 trial such practices were used in conjunction with the RTS, S based malaria vaccine.
- clinical episodes of malaria may for example be required to have the presence of P '. falciparum asexual parasitemia above 500 or above 0 per ⁇ L on Giemsa stained thick blood films and the presence of fever (temperature >37.5°C).
- severe malaria may, for example include the presence of one or more of the following: severe malaria anaemia (PCV ⁇ 15%), cerebral malaria (Blantyre coma score ⁇ 2 ) or severe disease of other body systems which could include multiple seizures (two or more generalized convulsions in the previous 24 hours), prostration (defined as inability to sit unaided), hypoglycaemia ⁇ 2.2mmol/dL or ⁇ 40mg/dL), clinically suspected acidosis or circulatory collapse.
- severe malaria anaemia PCV ⁇ 15%)
- cerebral malaria Cere.g., cerebral malaria
- prostration defined as inability to sit unaided
- hypoglycaemia ⁇ 2.2mmol/dL or ⁇ 40mg/dL
- clinically suspected acidosis or circulatory collapse e.glycaemia
- an aqueous solution of the purified hybrid protein may be used directly and combined with a suitable adjuvant or carrier.
- the protein can be lyophilized prior to mixing with a suitable adjuvant or carrier.
- a suitable vaccine dose in accordance with the invention is between 1-100 ⁇ g antigen e.g. RTS, S per dose, such as 5 to 75 ⁇ g of antigen eg RTS, S, particularly a dose of 25 ⁇ g of antigen eg RTS, S protein, for example in 250 to 500 ⁇ l (final liquid formulation).
- S per dose such as 5 to 75 ⁇ g of antigen eg RTS, S, particularly a dose of 25 ⁇ g of antigen eg RTS, S protein, for example in 250 to 500 ⁇ l (final liquid formulation).
- a particularly suitable dose of antigen for pediatric formulations according to the invention is 25 ⁇ g, for example in a final volume of 0.5 ml.
- the antigen is combined with an adjuvant or carrier.
- an adjuvant is present, such as an adjuvant which is a preferential stimulator of a ThI type response.
- Suitable adjuvants include but not limited to, detoxified lipid A from any source and nontoxic derivatives of lipid A, saponins and other immunostimulants which are preferential stimulators of a ThI cell response (also herein called a ThI type response).
- An immune response may be broadly divided into two extreme categories, being a humoral or cell mediated immune response (traditionally characterised by B lymphocytes producing antigen specific antibodies and T lymphocytes acting as antigen specific cellular effectors of protection.
- THl type responses (favouring the cell mediated effector immune responses) and TH2 type response (favouring the induction of antibody response).
- Extreme THl -type immune responses may be characterised by the generation of antigen specific, haplotype restricted cytotoxic T lymphocytes, and natural killer cell responses.
- THl-type responses are often characterised by the generation of antibodies of the IgG2a subtype, whilst in the human these correspond to IgGl type antibodies.
- TH2-type immune responses are characterised by the generation of a range of immunoglobulin isotypes including in mice IgGl.
- cytokines the driving force behind the development of these two types of immune responses.
- High levels of THl -type cytokines tend to favour the induction of cell mediated immune responses to the given antigen, whilst high levels of TH2-type cytokines tend to favour the induction of humoral immune responses to the antigen.
- THl and TH2-type immune responses are not absolute, and can take the form of a continuum between these two extremes. In reality an individual will support an immune response which is described as being predominantly THl or predominantly TH2. However, it is often convenient to consider the families of cytokines in terms of that described in murine CD4 positive T cell clones by Mosmann and Coffman ⁇ Mosmann, T.R. and Coffman, R.L. (1989) THl and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annual Review of Immunology, 7, pi 45- 173). Traditionally, THl -type responses are associated with the production of the INF- ⁇ cytokines by T-lymphocytes.
- cytokines often directly associated with the induction of THl-type immune responses are not produced by T-cells, such as IL-12.
- TH2- type responses are associated with the secretion of IL-4, IL-5, IL-6, IL-IO and tumour necrosis factor- ⁇ (TNF- ⁇ ).
- indicators of the THl :TH2 balance of the immune response after a vaccination or infection includes direct measurement of the production of THl or TH2 cytokines by T lymphocytes in vitro after restimulation with antigen, and/or the measurement (at least in mice) of the IgGl :IgG2a ratio of antigen specific antibody responses.
- a THl -type adjuvant is one which stimulates isolated T-cell populations to produce high levels of THl -type cytokines when re- stimulated with antigen in vitro, and induces antigen specific immunoglobulin responses associated with THl-type isotype.
- Adjuvants which are capable of preferential stimulation of the THl cell response are described in WO 94/00153 and WO 95/17209.
- ThI -type immuno stimulants which may be formulated to produce adjuvants suitable for use in the present invention include and are not restricted to the following.
- enterobacterial lipopolysaccharide is a potent stimulator of the immune system, although its use in adjuvants has been curtailed by its toxic effects.
- LPS enterobacterial lipopolysaccharide
- MPL monophosphoryl lipid A
- a further detoxified version of MPL results from the removal of the acyl chain from the 3-position of the disaccharide backbone, and is called 3-O-Deacylated monophosphoryl lipid A (3D-MPL). It can be purified and prepared by the methods taught in GB 2122204B, which reference also discloses the preparation of diphosphoryl lipid A, and 3- O-deacylated variants thereof.
- a preferred form of 3D-MPL is in the form of an emulsion having a small particle size less than 0.2 ⁇ m in diameter, and its method of manufacture is disclosed in WO 94/21292.
- Aqueous formulations comprising monophosphoryl lipid A and a surfactant have been described in WO 98/43670.
- the bacterial lipopolysaccharide derived adjuvants to be used in the present invention may be purified and processed from bacterial sources, or alternatively they may be synthetic.
- purified monophosphoryl lipid A is described in Ribi et al 1986 (supra), and 3-0-Deacylated monophosphoryl or diphosphoryl lipid A derived from
- Salmonella sp. is described in GB 2220211 and US 4912094.
- Other purified and synthetic lipopolysaccharides have been described (Hilgers et al., 1986, Int. Arch. Allergy. Immunol., 79(4):392-6; Hilgers et al., 1987, Immunology, 60(1): 141-6; and EP 0 549 074 Bl).
- a particularly preferred bacterial lipopolysaccharide adjuvant is 3D-MPL.
- the LPS derivatives that may be used in the present invention are those immunostimulants that are similar in structure to that of LPS or MPL or 3D-MPL.
- the LPS derivatives may be an acylated monosaccharide, which is a sub-portion to the above structure of MPL.
- Saponins are also suitable ThI immunostimulants in accordance with the invention. Saponins are well known adjuvants and are taught in: Lacaille-Dubois, M and Wagner H. (1996. A review of the biological and pharmacological activities of saponins. Phytomedicine vol 2 pp 363-386). For example, Quil A (derived from the bark of the South American tree Quillaja Saponaria Molina), and fractions thereof, are described in US 5,057,540 and "Saponins as vaccine adjuvants", Kensil, C. R., Crit Rev Ther Drug Carrier Syst, 1996, 12 (1-2): 1-55; and EP 0 362 279 Bl.
- haemolytic saponins QS21 and QS 17 HPLC purified fractions of Quil A
- QS7 a non- haemolytic fraction of Quil- A
- Use of QS21 is further described in Kensil et al. (1991. J. Immunology vol 146, 431-437).
- Combinations of QS21 and polysorbate or cyclodextrin are also known (WO 99/10008).
- Particulate adjuvant systems comprising fractions of QuilA, such as QS21 and QS7 are described in WO 96/33739 and WO 96/11711.
- CpG immunostimulatory oligonucleotide containing unmethylated CpG dinucleotides
- CpG is an abbreviation for cytosine- guanosine dinucleotide motifs present in DNA.
- CpG is known in the art as being an adjuvant when administered by both systemic and mucosal routes (WO 96/02555, EP 468520, Davis et al, J.Immunol, 1998, 160(2): 870-876; McCluskie and Davis,
- the immunostimulatory sequence is often: Purine, Purine, C, G, pyrimidine, pyrimidine; wherein the CG motif is not methylated, but other unmethylated CpG sequences are known to be immunostimulatory and may be used in the present invention.
- a palindromic sequence is present.
- Several of these motifs can be present in the same oligonucleotide.
- the presence of one or more of these immunostimulatory sequences containing oligonucleotides can activate various immune subsets, including natural killer cells (which produce interferon ⁇ and have cytolytic activity) and macrophages (Wooldrige et al VoI 89 (no. 8), 1977).
- natural killer cells which produce interferon ⁇ and have cytolytic activity
- macrophages Wangrige et al VoI 89 (no. 8), 1977.
- Other unmethylated CpG containing sequences not having this consensus sequence have also now been shown to be immunomodulatory.
- CpG when formulated into vaccines is generally administered in free solution together with free antigen (WO 96/02555; McCluskie and Davis, supra) or covalently conjugated to an antigen (WO 98/16247), or formulated with a carrier such as aluminium hydroxide ((Hepatitis surface antigen) Davis et al. supra ; Brazolot-Millan et al., Proc.Natl.Acad.ScL, USA, 1998, 95(26), 15553-8).
- a carrier such as aluminium hydroxide ((Hepatitis surface antigen) Davis et al. supra ; Brazolot-Millan et al., Proc.Natl.Acad.ScL, USA, 1998, 95(26), 15553-8).
- Such immunostimulants as described above may be formulated together with carriers, such as for example liposomes, oil in water emulsions, and/or metallic salts, including aluminium salts (such as aluminium hydroxide).
- carriers such as for example liposomes, oil in water emulsions, and/or metallic salts, including aluminium salts (such as aluminium hydroxide).
- 3D-MPL may be formulated with aluminium hydroxide (EP 0 689 454) or oil in water emulsions (WO 95/17210);
- QS21 may be advantageously formulated with cholesterol containing liposomes (WO 96/33739), oil in water emulsions (WO 95/17210) or alum (WO 98/15287);
- CpG may be formulated with alum (Davis et al. supra ; Brazolot-Millan supra) or with other cationic carriers.
- Combinations of immunostimulants are also preferred, in particular a combination of a monophosphoryl lipid A and a saponin derivative (WO 94/00153; WO 95/17210; WO 96/33739; WO 98/56414; WO 99/12565; WO 99/11241), more particularly the combination of QS21 and 3D-MPL as disclosed in WO 94/00153.
- a combination of CpG plus a saponin such as QS21 also forms a potent adjuvant for use in the present invention.
- suitable adjuvant systems include, for example, a combination of monophosphoryl lipid A, preferably 3D-MPL, together with an aluminium salt.
- An enhanced system involves the combination of a monophosphoryl lipid A and a saponin derivative particularly the combination of QS21 and 3D-MPL as disclosed in WO 94/00153, or a less reactogenic composition where the QS21 is quenched in cholesterol containing liposomes (DQ) as disclosed in WO 96/33739.
- a particularly potent adjuvant formulation involving QS21 , 3D-MPL & tocopherol in an oil in water emulsion is described in WO 95/17210 and is another preferred formulation for use in the invention.
- Another preferred formulation comprises a CpG oligonucleotide alone or together with QS21 , 3D-MPL or together with an aluminium salt.
- lipid A or a non-toxic derivative of lipid A, more preferably monophosphoryl lipid A or derivative thereof such as 3D-MPL, in combination with a malaria antigen as described herein, for the manufacture of a vaccine for the prevention of malaria disease and/or infection in infants.
- a saponin such as QS21
- a malaria antigen as described herein, for the manufacture of a vaccine for the prevention of malaria disease and/or infection in infants or a method of treating an infant employing the same.
- the invention provides use of detoxified lipid A or a non-toxic derivative of lipid A, more preferably monophosphoryl lipid A or derivative thereof such as 3D-MPL, in combination with a saponin, such as QS21, and a malaria antigen as described herein, for the manufacture of a vaccine for the prevention of malaria disease and/or infection in infants.
- a saponin such as QS21
- a malaria antigen as described herein
- the invention further employs an oil in water emulsion or liposomes.
- Suitable combinations of adjuvants for use in the present invention are:
- the amount of 3D-MPL used is generally small, but depending on the vaccine formulation may be in the region of l-1000 ⁇ g per dose, generally l-500 ⁇ g per dose, such as between 1 to lOO ⁇ g per dose (10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80 or 90 ⁇ g per dose).
- the amount of saponin for use in the adjuvants of the present invention may be in the region of l-1000 ⁇ g per dose, generally l-500 ⁇ g per dose, more such as l-250 ⁇ g per dose, and more specifically between 1 to lOO ⁇ g per dose (10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80 or 90 ⁇ g per dose).
- the amount of CpG or immunostimulatory oligonucleotides in the adjuvants or vaccines of the present invention is generally small, but depending on the vaccine formulation may be in the region of l-1000 ⁇ g per dose, generally l-500 ⁇ g per dose, and more such as between 1 to lOO ⁇ g per dose (10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80 or 90 ⁇ g per dose).
- the dose has a final volume of 0.5 ml.
- the vaccines of the invention may be provided by any of a variety of routes such as oral, topical, subcutaneous, mucosal), intravenous, intramuscular, intranasal, sublingual and intradermal.
- Immunisation can be prophylactic or therapeutic.
- the invention described herein is primarily but not exclusively concerned with prophylactic vaccination against malaria, more particularly prophylactic vaccination to prevent or to reduce the likelihood of malarial infection and/or malaria disease.
- Appropriate pharmaceutically acceptable carriers or excipients for use in the invention are well known in the art and include for example water or buffers.
- Vaccine preparation is generally described in Pharmaceutical Biotechnology, Vol.61 Vaccine Design - the subunit and adjuvant approach, edited by Powell and Newman, Plenum Press New York, 1995. New Trends and Developments in Vaccines, edited by Voller et al., University Park Press, Baltimore, Maryland, U.S.A. 1978.
- Encapsulation within liposomes is described, for example, by Fullerton, U.S. Patent 4,235,877.
- Conjugation of proteins to macromolecules is disclosed, for example, by Likhite, U.S. Patent 4,372,945 and by Armor et al., U.S. Patent
- Taninga two communities about 50 km north of the town of Manhica, where CISM headquarters are located. Characteristics of the overall study area and of Ilha Josina have been previously described (Alonso PL, Sacarlal J, Aponte JJ, Leach A, Macete E, Milman
- Taninga is a rural community facing Ilha Jossina directly across the flood plain of the Incomati River.
- the climate is subtropical with two distinct seasons: a warm and rainy season from November to April and a generally cool and drier season during the rest of the year.
- Malaria transmission is perennial with some seasonality and mostly attributable to P. falciparum.
- Anopheles funestus is the main vector.
- Combination therapy based on amodiaquine and sulphadoxine-pirimethamine was the first line treatment for uncomplicated malaria until September 2006 when it was changed to artemisinin based combination therapy (ACT) using artesunate and sulphadoxine-pyrimethamine.
- ACT artemisinin based combination therapy
- IRS indoor residual spraying
- the protocol was approved by the Mozambican National Bioethics Committee, the Hospital Clinic of Barcelona Ethics Review Committee and the PATH Human Subjects Protection Committee.
- Trial registration number is NCT00197028 and IND number is BB-IND 10514.
- CISM operates a demographic surveillance system in about half of the district which includes both study locations.
- An information sheet was read and explained to groups of pregnant women by specially trained staff.
- a member of the community not associated with the research study, acted as an impartial witness and countersigned the consent form.
- HIV AIDS HBsAg, Abbot Laboratories
- Women found to be HIV positive were referred to the government health services at the Manhica District Hospital for medical evaluation and management following National Guidelines. These included reduction of mother to child transmission as well as the free provision of anti-retro viral therapy to those fulfilling clinical and social criteria.
- Hepatitis B positive mothers were counselled about the risk of transmission to the offspring and Hepatitis B vaccine at birth was offered to the newborn.
- infants were screened between 6 and 12 weeks of age. This included a brief medical history and physical examination and blood sampling by heel prick or venous puncture for baseline haematology, biochemistry and immunology. Inclusion criteria included, among others, a normal gestational period and absence of obvious medical abnormalities. Because children born to Hepatitis B and HIV-positive mothers are at a high risk of neonatal acquisition of the viruses, they were not included in the trial. Among other criteria, children were excluded from participation if BCG was not given at least one week before starting study vaccination or if any other vaccinations, other than the first dose of OPV given at birth with BCG, had been given prior to enrolment.
- EPI in Mozambique includes BCG vaccine and Oral Polio Vaccine (OPV) at birth, three doses of Dipheteria-Tetanus-Pertusis whole cell (DTPw) and Hepatitis B vaccines, coadministered with OPV at 8, 12 and 16 weeks of age and measles vaccine at 9 months of age.
- DTPw Dipheteria-Tetanus-Pertusis whole cell
- Hepatitis B vaccines coadministered with OPV at 8, 12 and 16 weeks of age and measles vaccine at 9 months of age.
- Hepatitis B vaccine was not given together with DTPw as RTS, S has been shown to induce comparable titers of anti- HBsAg.
- Figure Ia represents the trial design and follow-up scheme. Eligible children were enrolled the day of the first vaccination with DTPw/Hib [TETRActHibTM Aventis Pasteur]. Children were randomly allocated, at the time of the first vaccination with DTPw/Hib, to receive three doses of either RTS,S/AS02D (GSK Biologicals, Rixensart.
- Hepatitis B vaccine (Engerix-BTM, GSK Biologicals, Rixensart, Belgium) staggered by 2 weeks with DTPw/Hib and OPV vaccines and administered at 10, 14 and 18 weeks of age.
- Block randomization was done at GSK Biologicals with SAS software version 8 (1 :1 ratio, block size of 2). The randomization code was released to the investigators once databases had been monitored, cleaned and locked.
- the infants randomised to the paediatric formulation of the malaria vaccine group received 0.5ml of the RTS,S/AS02D formulation containing 25 ⁇ g of RTS, S and the Adjuvant System AS02D.
- RTS, S is a hybrid recombinant protein consisting of the P. falciparum CS protein central tandem repeat and carboxy-terminal regions fused to the amino-terminus of the S antigen of hepatitis B virus (HBsAg).
- the proteins auto- assemble to form a particle that also includes unfused S antigen.
- DTPw/Hib was administered by the intramuscular (IM) route in the right antero-lateral thigh while RTS,S/AS02D or Engerix-BTM were administered IM in the left antero-lateral thigh.
- the RTS,S/AS02D or Engerix-BTM vaccination was delivered in a double blind fashion (observer blinded, participant blinded).
- the vaccination team prepared the vaccine and masked the contents of the syringe with opaque tape before providing the syringe to the clinical team for immunisation of the infant. Since the two vaccines used in the study were of distinct appearance, the vaccination team was not blinded and was not involved in any other study procedure.
- Anti-HBsAg antibody titres were measured at baseline and one month post dose 3 of RTS,S/AS02D or Engerix-BTM.
- Anti-CS antibody titres were measured at baseline, and one and three and a half months post dose 3 of RTS,S/AS02D or Engerix-BTM.
- Antibodies against diphtheria and tetanus toxins and polyribosyl ribitol phosphate (PRP) for H. influenzae type b were measured one month after dose 3 of DTPw/Hib.
- Antibodies against B. pertussis were measured at baseline and one month after the 3rd dose of DTPw/Hib. Cases of malaria infection by P.
- ADI active detection of infection
- PCD passive case detection
- asymptomatic parasitaemia was cleared presumptively in all children with a combination of amodiaquine (10mg/kg/day for 3 days) and a single dose of sulfadoxine -pyrimethamine (sulfadoxine 25mg/kg and pyrimethamine 1,25 mg/kg) administered two weeks prior to the third and final dose of RTS,S/AS02D or Engerix- BTM.
- Parasitaemia was checked 2 weeks later at the time of the third dose and, if present, treated with second-line treatment based on Coartem . Only children without parasitemia started the ADI, which commenced 2 weeks after the third dose of RTS,S/AS02D or Engerix-BTM and was performed every-other week for 12 weeks.
- the health facility based morbidity surveillance system set up at the Manhica District Hospital, Ilha Josina and Taninga health posts, enabled passive case detection (PCD) of all attendances to health facilities and ascertainment of episodes of clinical malaria.
- PCD passive case detection
- This surveillance system has been described in detail elsewhere (Alonso PL, Sacarlal J, Aponte JJ, Leach A, Macete E, Milman J, et al. Efficacy of the RTS,S/AS02A vaccine against Plasmodium falciparum infection and disease in young African children: randomised controlled trial. Lancet 2004 Oct 16-22;364(9443): 1411-20).
- the three facilities have 24h medical staff trained to identify study participants through the personal identification card and to ensure standardized assessment, management and documentation throughout follow-up. All children with documented fever (37.5 0 C or more) or history of fever in the preceding 24h, or pallor had blood taken for parasite and packed cell volume (PCV) determinations. Children meeting admission criteria were referred to the Manhica District Hospital for hospitalization. Clinical management was provided according to standard national guidelines. On admission and discharge all relevant information was recorded on standardised forms.
- PCV packed cell volume
- Antibodies specific for the CS protein tandem repeat epitope were measured by a standard ELISA using plates absorbed with the recombinant antigen R32LR that contains the sequence [NVDP(NANP) 15]2LR.
- the assay cut-off was set at 0.5 EU/ml.
- Anti- HBsAg antibody levels were measured using a commercial radioimmunoassay (AUSAB, Abbott) with an assay cut-off set at 10 IU/ml.
- Anti-PRP antibodies were measured by ELISA with a cut-off set at 0.15 ⁇ g/ml.
- Anti-diphtheria and anti-tetanus antibodies titres were measured by ELISA with an assay cut-off set at 0.10 IU/ml.
- Anti-whole-cell-B. Pertussis antibody titres were determined by ELISA (Labsystems) with an assay cut-off set at 15 EL.U/ml.
- the primary endpoints of the trial were safety and tolerability of the RTS,S/AS02D vaccine candidate. All children who received at least one dose of DTPw/Hib were included in the intention-to-treat (ITT) safety analysis.
- Anti-CS and anti-HBsAg antibody data were summarised by Geometric Mean Titres (GMTs) with 95% CI.
- Anti-CS seropositivity was defined as > 0.5 EU/ml, while seroprotection from Hepatitis B was defined as > 10 IU/ml.
- the test of concept for vaccine efficacy was based on a prospectively-defined Report & Analysis Plan (RAP) carried out on an According to Protocol (ATP) cohort.
- the ATP cohort included subjects that met all eligibility criteria, completed the vaccination course and contributed follow-up time during the ADI period.
- the analysis included all first or only asexual P. falciparum infections detected during the follow-up period starting 14 days after dose 3 of RTS,S/AS02D or Engerix-BTM and ending with the visit at study month 6 (approximately a 3 month follow-up). Malaria infections included in this analysis were detected by ADI or PCD.
- exploratory analysis considered vaccine efficacy against clinical malaria in an ITT cohort that included first or only episodes from the time of enrolment until the date on which the last enrolled infant completed their ADI follow-up (March 6 l 2007). Additionally, exploratory analyses of clinical malaria were performed in the same ATP cohort and follow-up period as in the efficacy assessment of new infections.
- the primary case definition for clinical malaria was fever (axillary temperature > 37.5 0 C) with an asexual parasitaemia of P '. falciparum of 500 or more per microliter. This definition has a reported sensitivity and specificity of greater than 90% (Saute F, Aponte J, Almeda J, Ascaso C, Abellana R, Vaz N, et al.
- VE was defined as 1 minus the rate ratio.
- Vaccine efficacy was adjusted by distance to health facility, calculated according to previously described methods (Alonso PL, Sacarlal J, Aponte JJ, Leach A, Macete E, Milman J, et al. Efficacy of the RTS,S/AS02A vaccine against Plasmodium falciparum infection and disease in young African children: randomised controlled trial. Lancet 2004 Oct 16-22;364(9443): 1411-20) and community of residence. The adjusted vaccine efficacy, assessed using Cox regression models, is reported throughout the text unless otherwise stated.
- the sample size was based on the evaluation of vaccine safety. A trial with 100 subjects in each group had 80% power to detect a difference in the proportion of adverse events of 26% or more if the frequency of an event in the Engerix-BTM group was 10% or more. A trial of this size also had 90% power to detect an efficacy against malaria infection of 45% or more assuming an attack rate of 75% or more in the control group over the surveillance period. Analyses were performed using SAS and STATA.
- Figure 1 shows the trial profile. 326 out of 446 pregnant women fulfilled the eligibility criteria and delivered 329 newborns. Of those, 251 infants were screened and 214 (85%) of the screened children were enrolled in the trial and received the first dose of DTPw/Hib vaccine. 93 (86%) of the children in the RTS,S/AS02D and 92 (85%) in the
- Engerix-BTM group entered ADI follow-up. During the follow-up, consent was withdrawn from seven children in the RTS,S/AS02D group and eight children in the
- Engerix-BTM group Three children in each group received the wrong vaccine at Dose 2 of RTS,S/AS02D or Engerix-BTM. They were not included in the ATP analysis. Baseline characteristics for both groups are presented in Table 1.
- Figure 2c shows the proportion of all administered doses where a solicited symptom was recorded.
- the figure presents four groups, as the data for DTPw/Hib and OPV are segregated by randomisation assignment. The proportion of children with pain was high and similar in all groups. The relative proportion of symptoms was similar after each injection of RTS,S/AS02D and comparable in magnitude (data not shown). No grade 3 solicited symptom was documented in the RTS,S/AS02D group, and the incidence was very low in the other groups (data not shown).
- ITT cohort followed until end of follow-up on 6 March 2007, there were 31 SAEs in the RTS,S/AS02D group and 30 SAEs in the Engerix-BTM group. None of them were reported as related to vaccination.
- Anti-CS and anti-HBsAg antibody levels measured against CS and HBsAg are shown in Table 2.
- Table 2 At screening 24/76 (32%) and 26/77 (34%) of the infants in the RTS,S/AS02D and Engerix-BTM group, respectively, had low titres of detectable anti-CS antibodies.
- Three and a half months after dose 3 (study month 6) the proportion of anti-CS positives in the RTS,S/AS02D remained high (98%) but the GMT had decreased.
- the anti-CS GMT in the Engerix-BTM group remained low, even though the prevalence of detectable antibodies increased to 20% (12/61). Response to hepatitis B was good in both groups (Table 2).
- Figure 4 shows the proportion of children with at least one episode of malaria infection during the ADI follow-up starting 14 days after dose 3 of RTS,S/AS02D or Engerix-BTM up to study month 6.
- a total of 68 new infection were documented during this follow-up period, 22 in the RTS,S/AS02D group and 46 in the Engerix-BTM group.
- Table 3 Vaccine efficacy from 14 days after third dose of Engerix-BTM or RTS.S/AS02D until visit at month 6
- PYAR Person-years at risk.
- Vaccine efficacy estimates adjusted by distance from health facility and community.
- PYAR Episodes/Person Years at Risk
- VE Vaccine Efficacy (1-HR)
- Cl Confidence Interval
- p value from Cox PH model Phase Change PH model
- Poisson regression for multiple episodes a first or only episodes
Abstract
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Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2010128524A3 (en) * | 2009-05-05 | 2011-03-24 | Cadila Healthcare Limited | Combined measles-malaria vaccine |
CN102268093A (en) * | 2011-06-27 | 2011-12-07 | 广东药学院 | Fusion protein of hepatic-targeted peptide and human interferon a2b, and preparation method and application thereof |
JP2013502417A (en) * | 2009-11-05 | 2013-01-24 | アメリカ合衆国 | Plasmodium falciparum sporozoites and liver stage antigens |
JP2013527760A (en) * | 2010-05-03 | 2013-07-04 | アンスティテュ パストゥール | Immunological compounds against malaria based on lentiviral vectors |
EP2621540A2 (en) * | 2010-09-27 | 2013-08-07 | The Trustees Of The University Of Pennsylvania | Consensus antigen constructs and vaccines made therefrom, and methods of using same to treat malaria |
JP2014511837A (en) * | 2011-03-25 | 2014-05-19 | アメリカ合衆国 | P. falciparum antigen |
US8889146B2 (en) | 2009-06-24 | 2014-11-18 | Glaxosmithkline Biologicals, Sa | Vaccine |
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006029887A2 (en) * | 2004-09-16 | 2006-03-23 | Glaxosmithkline Biologicals Sa | Vaccines comprising plasmodium antigens |
WO2007003384A1 (en) * | 2005-06-30 | 2007-01-11 | Glaxosmithkline Biologicals Sa | Anti-malaria vaccine |
Family Cites Families (38)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4235877A (en) | 1979-06-27 | 1980-11-25 | Merck & Co., Inc. | Liposome particle containing viral or bacterial antigenic subunit |
US4372945A (en) | 1979-11-13 | 1983-02-08 | Likhite Vilas V | Antigen compounds |
IL61904A (en) | 1981-01-13 | 1985-07-31 | Yeda Res & Dev | Synthetic vaccine against influenza virus infections comprising a synthetic peptide and process for producing same |
DE3280028D1 (en) | 1981-05-21 | 1989-12-28 | Wellcome Found | Protozoal antigen |
US4436727A (en) | 1982-05-26 | 1984-03-13 | Ribi Immunochem Research, Inc. | Refined detoxified endotoxin product |
US5057540A (en) | 1987-05-29 | 1991-10-15 | Cambridge Biotech Corporation | Saponin adjuvant |
CA1331443C (en) | 1987-05-29 | 1994-08-16 | Charlotte A. Kensil | Saponin adjuvant |
US4912094B1 (en) | 1988-06-29 | 1994-02-15 | Ribi Immunochem Research Inc. | Modified lipopolysaccharides and process of preparation |
GB8819209D0 (en) | 1988-08-12 | 1988-09-14 | Research Corp Ltd | Polypeptide & dna encoding same |
GB9002512D0 (en) | 1990-02-05 | 1990-04-04 | 3I Res Expl Ltd | Polypeptides and dna encoding same |
GB9012580D0 (en) | 1990-06-06 | 1990-07-25 | Univ Nijmegen | Novel protein |
EP0468520A3 (en) | 1990-07-27 | 1992-07-01 | Mitsui Toatsu Chemicals, Inc. | Immunostimulatory remedies containing palindromic dna sequences |
US5198535A (en) | 1991-01-10 | 1993-03-30 | The United States Of America As Represented By The Secretary Of The Navy | Protective malaria sporozoite surface protein immunogen and gene |
DE69228698T2 (en) | 1991-11-16 | 1999-09-16 | Smithkline Beecham Biolog | HYBRID PROTEIN BETWEEN PLASMODIUM AND HBsAG |
JP3723231B2 (en) | 1991-12-23 | 2005-12-07 | ディミナコ アクチェンゲゼルシャフト | Adjuvant |
EP0761231B1 (en) | 1992-06-25 | 2000-01-12 | SMITHKLINE BEECHAM BIOLOGICALS s.a. | Vaccine composition containing adjuvants |
AU685443B2 (en) | 1993-03-23 | 1998-01-22 | Smithkline Beecham Biologicals (Sa) | Vaccine compositions containing 3-O deacylated monophosphoryl lipid A |
GB9326253D0 (en) | 1993-12-23 | 1994-02-23 | Smithkline Beecham Biolog | Vaccines |
ES2267100T5 (en) | 1994-07-15 | 2011-04-08 | The University Of Iowa Research Foundation | IMMUNOMODULATING OLIGONUCLEOTIDES. |
AUPM873294A0 (en) | 1994-10-12 | 1994-11-03 | Csl Limited | Saponin preparations and use thereof in iscoms |
UA56132C2 (en) | 1995-04-25 | 2003-05-15 | Смітклайн Бічем Байолоджікалс С.А. | Vaccine composition (variants), method for stabilizing qs21 providing resistance against hydrolysis (variants), method for manufacturing vaccine |
GB9620795D0 (en) | 1996-10-05 | 1996-11-20 | Smithkline Beecham Plc | Vaccines |
GB9616351D0 (en) | 1996-08-02 | 1996-09-11 | Smithkline Beecham Biolog | Vaccine composition |
US6083716A (en) | 1996-09-06 | 2000-07-04 | The Trustees Of The University Of Pennsylvania | Chimpanzee adenovirus vectors |
US6610661B1 (en) | 1996-10-11 | 2003-08-26 | The Regents Of The University Of California | Immunostimulatory polynucleotide/immunomodulatory molecule conjugates |
CA2285330C (en) | 1997-03-29 | 2005-06-07 | Ji Hoon Park | Continuous injecting apparatus |
GB9711990D0 (en) | 1997-06-11 | 1997-08-06 | Smithkline Beecham Biolog | Vaccine |
ES2500490T3 (en) | 1997-08-29 | 2014-09-30 | Antigenics Inc. | Compositions comprising adjuvant QS-21 and polysorbate or cyclodextrin as excipient |
ES2298316T3 (en) | 1997-09-05 | 2008-05-16 | Glaxosmithkline Biologicals S.A. | WATER OIL EMULSIONS CONTAINING SAPONINS. |
GB9718901D0 (en) | 1997-09-05 | 1997-11-12 | Smithkline Beecham Biolog | Vaccine |
AU2002306896B2 (en) | 2001-03-26 | 2007-04-26 | Walter Reed Army Institute Of Research | Plasmodium falciparum AMA-1 protein and uses thereof |
AU2002360429A1 (en) | 2001-11-26 | 2003-06-10 | Avigen, Inc. | Methods for producing stocks of recombinant aav virions |
PL376792A1 (en) | 2002-10-23 | 2006-01-09 | Glaxosmithkline Biologicals S.A. | Methods for vaccinating against malaria |
EP1569674B1 (en) | 2002-11-12 | 2014-12-24 | Walter Reed Army Institute of Research | Expression, purification and uses of a plasmodium falciparum liver stage antigen 1 polypeptide |
PL1802336T3 (en) | 2004-10-14 | 2012-03-30 | Crucell Holland Bv | Malaria prime/boost vaccines |
EP1754717A1 (en) | 2005-08-19 | 2007-02-21 | Université de Lausanne | Antigenic peptides and their use |
AR067905A1 (en) | 2007-08-13 | 2009-10-28 | Glaxosmithkline Biolog Sa | VACCINES |
US9821046B2 (en) * | 2013-01-21 | 2017-11-21 | Oxford University Innovation Limited | Composition and uses thereof |
-
2008
- 2008-08-11 AR ARP080103497A patent/AR067905A1/en not_active Application Discontinuation
- 2008-08-11 TR TR2018/02221T patent/TR201802221T4/en unknown
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- 2008-08-11 US US12/673,272 patent/US9066899B2/en active Active
- 2008-08-11 EP EP08787080.4A patent/EP2190470B1/en active Active
- 2008-08-11 CA CA2695477A patent/CA2695477A1/en active Pending
- 2008-08-11 CL CL2008002361A patent/CL2008002361A1/en unknown
- 2008-08-11 UY UY31285A patent/UY31285A1/en unknown
- 2008-08-11 AU AU2008288508A patent/AU2008288508B2/en not_active Ceased
- 2008-08-11 AP AP2010005166A patent/AP2010005166A0/en unknown
- 2008-08-11 KR KR1020107005518A patent/KR20100068390A/en active IP Right Grant
- 2008-08-11 NZ NZ583150A patent/NZ583150A/en not_active IP Right Cessation
- 2008-08-11 TW TW097130604A patent/TW200924791A/en unknown
- 2008-08-11 ES ES08787080.4T patent/ES2658347T3/en active Active
- 2008-08-11 JP JP2010520550A patent/JP5508266B2/en active Active
- 2008-08-11 WO PCT/EP2008/060505 patent/WO2009021931A1/en active Application Filing
- 2008-08-11 MX MX2010001752A patent/MX2010001752A/en active IP Right Grant
-
2010
- 2010-02-11 ZA ZA2010/01029A patent/ZA201001029B/en unknown
- 2010-02-11 DO DO2010000056A patent/DOP2010000056A/en unknown
- 2010-03-08 MA MA32675A patent/MA31693B1/en unknown
- 2010-03-10 CR CR11307A patent/CR11307A/en unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006029887A2 (en) * | 2004-09-16 | 2006-03-23 | Glaxosmithkline Biologicals Sa | Vaccines comprising plasmodium antigens |
WO2007003384A1 (en) * | 2005-06-30 | 2007-01-11 | Glaxosmithkline Biologicals Sa | Anti-malaria vaccine |
Non-Patent Citations (6)
Title |
---|
ACOSTA C J ET AL: "Evaluation of the SPf66 vaccine for malaria control when delivered through the EPI scheme in Tanzania", TROPICAL MEDICINE AND INTERNATIONAL HEALTH, vol. 4, no. 5, May 1999 (1999-05-01), pages 368 - 376, XP002501761, ISSN: 1360-2276 * |
ALONSO ET AL: "Duration of protection with RTS,S/AS02A malaria vaccine in prevention of Plasmodium falciparum disease in Mozambican children: single-blind extended follow-up of a randomised controlled trial", LANCET THE, LANCET LIMITED. LONDON, GB, vol. 366, no. 9502, 10 December 2005 (2005-12-10), pages 2012 - 2018, XP005204961, ISSN: 0140-6736 * |
ALONSO ET AL: "Efficacy of the RTS,S/AS02A vaccine against Plasmodium falciparum infection and disease in young African children: randomised controlled trial", LANCET THE, LANCET LIMITED. LONDON, GB, vol. 364, no. 9443, 16 October 2004 (2004-10-16), pages 1411 - 1420, XP005106739, ISSN: 0140-6736 * |
ALONSO P L ET AL: "Randomised trial of efficacy of SPf66 vaccine against Plasmodium falciparum malaria in children in southern Tanzania", LANCET (NORTH AMERICAN EDITION), vol. 344, no. 8931, 1994, pages 1175 - 1181, XP002501760, ISSN: 0099-5355 * |
GRAVES, P., GELBAND H: "vACCINES FOR PREVENTING MALARIA (spf66) (review)", COCHRANE DATABASE OF SYSTEMATIC REVIEWS, no. 2, 19 April 2006 (2006-04-19), XP002501762, Retrieved from the Internet <URL:http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD005966/pdf_fs.html> [retrieved on 20081029] * |
SACARLAL ET AL: "Safety of the RTS,S/AS02A malaria vaccine in Mozambican children during a Phase IIb trial", VACCINE, BUTTERWORTH SCIENTIFIC. GUILDFORD, GB, vol. 26, no. 2, 26 November 2007 (2007-11-26), pages 174 - 184, XP022394776, ISSN: 0264-410X * |
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CL2008002361A1 (en) | 2009-08-07 |
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EP2190470B1 (en) | 2017-12-13 |
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JP5508266B2 (en) | 2014-05-28 |
BRPI0815199A2 (en) | 2015-03-31 |
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